According to the World Health Organization, in the year 2002, 5 million people worldwide were newly infected with the human immunodeficiency virus (HIV) resulting in a total of 42 million people living with HIV or the acquired autoimmune deficiency syndrome (AIDS). Like many other infections, HIV triggers a response by the immune system via the massive production of antigen-recognizing antibodies (Abs). However, ultimately the immune system fails to control the virus, leading to the onset of AIDS. In some cases, patients develop neutralizing Abs and, consequently, do not develop AIDS. These neutralizing Abs have been shown to primarily target viral surface proteins. The antigenic proteins are expressed as the env-protein gp160 which is subsequently cleaved into the envelope glycoprotein gp120 and the transmembrane protein gp41. Some regions of the mature proteins are exposed by conformational changes during certain stages of infection or in viral debris, and induce formation of neutralizing Abs. The regions recognized by neutralizing Abs are of special interest in respect to developing drugs or vaccines that inhibit infection by HIV. Additionally, information about the interacting surfaces in the protein complexes actively involved in the infection process can also lead to vaccine candidates as well as a better understanding of the process itself. The biophysical characterization of the surfaces of interaction in protein complexes, such as antibody:antigen, should provide insight into how proteins recognize their binding partners and should aid in understanding how these molecules fulfill their in vivo functions. Therefore, the central research program of the MS Workgroup has been to develop and apply mass spectrometry-based techniques to determining the interaction surfaces in protein complexes. The specific interactions we are characterizing include: interactions of HIV rgp120/gp41 with human in vivo broadly neutralizing anti-HIV monoclonal antibodies; and HIV rp24 interactions with MAbs.